With the decoding of the human and other genomes, the paradigm of drug discovery is expected to change to one that is focused on molecular design for interaction with specific proteins. This new emphasis on proteomics will require experimental verification of the details of protein/ligand interactions under a wide variety of conditions. Current techniques either require formation of single crystals of sufficient quality of the protein/ligand complex for x-ray diffraction work or else interpretation of NMR spectra. This work is difficult as indicated by a cursory examination of the Protein Data Base that shows only about 10% of the entries involve protein/ligand complexes.
Present screening methods for protein-ligand interaction often involve either: (1) the selective displacement of a dye molecule by the ligand thus provoking a change in the optical spectrum; or (2) performance of detailed single crystal structure determinations on every potential protein-ligand complex to determine the presence or absence of the ligand molecule in the protein structure. The former method requires selection and development of a suitable dye that interacts with the protein in the same way a presumed ligand might interact. Dyes that interact in different ways will not show a clear and definitive test for a ligand binding in the active site of the protein. In the latter method, the fundamental requirements for the single crystal test involve the ability to produce quantities of suitable single crystals for the ligand binding tests and that the single crystal survives the formation of the protein-ligand complex. As these two requirements are frequently not fulfilled for a chosen protein target, a quicker, more robust method has been desirable for detecting or screening possible interactions between a selected target macromolecule or protein and a suite of possible small molecule ligands.
It is an object of the present invention to provide a process for process that can be used to detect or screen possible interactions between a selected target macromolecule or protein and a suite of possible small molecule ligands.